Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are photoreceptor diseases that cause substantial vision loss and lead to subsequent blindness in over 15 million people worldwide. After the loss of the photoreceptor layer, the spatial organization of the inner nuclear and ganglion cell layers can become disorganized and inner nuclear and ganglion cell layers begin to thin. However, the inner nuclear and ganglion cell layers maintain relatively high cell density and some functional circuitry remains. These findings of residual function within the inner layers of the retina have inspired a variety of research focused on sight restoration technologies that interface with remaining retinal cells.
A great deal of progress has been made in treating one type of RP (i.e., Leber's Congenital Amaurosis; RPE65 mutation) using a gene replacement therapy. However, current gene therapies focused on restoring function within photoreceptors necessarily require the maintenance of photoreceptors and are specific to a single gene mutation gene mutation. This limits the utility of this approach for many types of RP since photoreceptor cells generally die off as a function of the disease process, and the genetics of RP is highly heterogeneous. Over 180 different gene mutations have been positively identified as being involved with photoreceptor disease and this number is likely an underestimate. One recent estimate is that there are likely to be over 400 gene mutations associated with photoreceptor disease.
A second approach to treatment is genetically targeting bipolar and/or ganglion cells with engineered photo-gates or light-sensitive proteins such as channelrhodopsin-2 (ChR2), which has the advantage of not needing to be specific to a given gene mutation. Still, ChR2 activation requires light stimulation levels that are 5 orders of magnitude greater than the threshold of cone photoreceptors and has a substantially limited dynamic range (2 log units). An ideal therapy would be able to treat blindness independent of the genetic mutation, in the absence of photoreceptors, and with reasonable response sensitivity.
One typical application of neural tissue stimulation is in the rehabilitation of the blind. Some forms of blindness involve selective loss of the light sensitive transducers of the retina. Other retinal neurons remain viable, however, and may be activated in the manner described above by placement of a prosthetic electrode device on the inner (toward the vitreous) retinal surface (epiretinal). This placement must be mechanically stable, minimize the distance between the device electrodes and the visual neurons, and avoid undue compression of the visual neurons.
In 1986, Bullara (U.S. Pat. No. 4,573,481) patented an electrode assembly for surgical implantation on a nerve. The matrix was silicone with embedded iridium electrodes. The assembly fit around a nerve to stimulate it.
Dawson and Radtke stimulated cat's retina by direct electrical stimulation of the retinal ganglion cell layer. These experimenters placed nine and then fourteen electrodes upon the inner retinal layer (i.e., primarily the ganglion cell layer) of two cats. Their experiments suggested that electrical stimulation of the retina with 30 to 100 uA current resulted in visual cortical responses. These experiments were carried out with needle-shaped electrodes that penetrated the surface of the retina (see also U.S. Pat. No. 4,628,933 to Michelson).
The Michelson '933 apparatus includes an array of photosensitive devices on its surface that are connected to a plurality of electrodes positioned on the opposite surface of the device to stimulate the retina. These electrodes are disposed to form an array similar to a “bed of nails” having conductors which impinge directly on the retina to stimulate the retinal cells. U.S. Pat. No. 4,837,049 to Byers describes spike electrodes for neural stimulation. Each spike electrode pierces neural tissue for better electrical contact. U.S. Pat. No. 5,215,088 to Norman describes an array of spike electrodes for cortical stimulation. Each spike pierces cortical tissue for better electrical contact.
The art of implanting an intraocular prosthetic device to electrically stimulate the retina was advanced with the introduction of retinal tacks in retinal surgery. De Juan, et al. at Duke University Eye Center inserted retinal tacks into retinas in an effort to reattach retinas that had detached from the underlying choroid, which is the source of blood supply for the outer retina and thus the photoreceptors. See, e.g., E. de Juan, et al., 99 Am. J. Ophthalmol. 272 (1985). These retinal tacks have proved to be biocompatible and remain embedded in the retina, and choroid/sclera, effectively pinning the retina against the choroid and the posterior aspects of the globe. Humayun, U.S. Pat. No. 5,935,155 describes the use of retinal tacks to attach a retinal array to the retina. Alternatively, an electrode array may be attached by magnets or glue. U.S. Pat. No. 5,109,844 to de Juan describes a flat electrode array placed against the retina for visual stimulation.
Any device for stimulating percepts in the retina must receive a signal describing a visual image along with power to operate the device. The device can not be powered by wires as any connection through the skin will create the risk of infection. Battery power is not practical as batteries are bulky and surgery is required to replace them. Such signal and power may be transmitted into the eye inductively as shown in Humayun U.S. Pat. No. 5,935,155. Humayun uses a primary (external) coil in front of the eye, possibly encased within the rim of a pair of glasses, and a secondary (internal) coil within the lens capsule or around the sclera just under the conjunctiva. Implanting within the lens capsule is difficult surgery and only allows for a small diameter coil. Larger coils are more efficient, can receive more power with less resulting temperature rise per unit of power received. Implanting around the sclera under the conjunctiva and near the surgical limbus (that is at the front of the eye) allows for a larger coil but may cause irritation or damage to the conjunctiva if the coil is placed in front near the cornea.
U.S. patent application Ser. No. 09/761,270, Ok, discloses several coil configurations including a configuration where the coil is offset about 45 degrees from the front of the eye. The offset configuration allows the primary and secondary coils to be placed closer together allowing for better inductive coupling. The bridge of nose partially blocks placement of a primary coil when placed directly in front of the eye.
A better configuration is needed allowing for close physical spacing of relatively large primary and secondary coils, without causing physical damages such as erosion of the conjunctiva.
Several groups have recently developed microelectronic retinal prostheses with the ultimate goal of restoring vision in blind subjects by stimulating the remaining retinal cells with spatiotemporal sequences of electrical pulses. Analogous to cochlear implants, these devices are designed to directly stimulate remaining retinal neurons with pulsing electrical current. To date, both semi-acute and long-term implanted devices have been demonstrated to be safe and capable of generating visual percepts in human subjects. Note, however, that only the Second Sight Argus trials have thus far allowed use of the system outside of the clinic in subject's daily lives. The ultimate goal of these projects is to generate useful vision in blind patients by presenting a spatial and temporal sequence of electrical pulses that represent meaningful visual information, such as a continuous video stream that uses electrical pulses rather than pixels.
Here we examine how systematic variations in spatiotemporal patterns of multi-electrode retinal stimulation influence the perceived brightness in our prosthesis patients. It is well known that for cochlear implants the precise timing of stimulation across electrodes has perceptual consequences as a result of both electrical field. However, to date, only limited data have been reported examining how electrodes interact during spatiotemporal stimulation in the retina. Earlier work from our group demonstrated significant interactions between pairs of electrodes, even when they are stimulated non-simultaneously. Here we systematically examined how these interactions affect perceived brightness and we present a simple computational model that describes these data.